Maternal and Newborn Polymorphisms in Phase I/II Metabolic Genes Contribute to Risk of Adverse Reproductive Outcomes

Maternal cigarette smoke exposure during pregnancy has been identified as a risk factor for adverse reproductive outcomes, a major public health concern. However, little is known about genetic susceptibility and possible interactions with environmental factors to increase risk of these events. This study was designed to investigate relative contributions of genetic and maternal environmental risk factor interactions to adverse reproductive outcomes. Maternal peripheral and umbilical cord blood samples from 1148 healthy mother/newborn pairs were genotyped for a panel of polymorphisms associated with the metabolic enzymes CYP1A1, CYP2E1, GSTM1, GSTT1 and NAT2* for several subgroups; low birthweight (<2500g, n=86), preterm delivery (<37th gestational week, n=93), premature birth (<2500g & <37th gestational week, n=53) and small for gestational age (SGA) at term („d37th gestational week, n=948) in comparison to the average for gestational age (AGA) group (n=948). Maternal cigarette smoking during the last trimester was significantly associated with birthweight reduction (ƒÝ=101.4g, SE=32, p=0.002). Maternal GSTT1 null genotype was significantly associated with low birthweight (OR=1.97, 95% CI: 1.24-3.12, p=0.004), preterm delivery (OR=1.91, 95% CI: 1.22-2.98, p=0.004) and premature birth (OR=2.42, 95% CI: 1.38-4.26, p=0.002). The mean reduction of birthweight observed among the maternal GSTT1 null genotype group was 89.6g (SE=37, p=0.018) and the mean reduction in gestational age was 0.25 weeks (SE=0.1, p=0.049). In addition, African American women were more likely to have a smaller baby; the mean reduction of birthweight was 230g (SE=34.5, p<0.001) compared with Caucasians. An additive interaction between smoking, African American ethnicity and GSTT1 null genotype was observed (OR=7.81, 95% CI: 2.49-24.43, p<0.001). The mean birthweight reduction observed in this group was 570.0g (SE=117, p<0.001) and the mean gestational age reduction was 1.10 weeks (SE=0.4, p=0.007). A similar risk was observed for newborn GSTT1 null genotype in the presence of maternal smoking (426.7g,SE=111, p<0.001) and (1.0 weeks, SE=0.4, p=0.012). These results demonstrated a clear overrepresentation of maternal and newborn GSTT1 null genotype among adverse reproductive outcome cases. Furthermore, a gene-gene-environment interaction was observed where the combination of maternal and newborn GSTT1 null genotype in the presence of maternal cigarette smoke during pregnancy significantly increased risk of adverse reproductive outcomes

Molecular characterization of human T-cell lymphotropic virus type 1 full and partial genomes by Illumina massively parallel sequencing technology.

Background\ud \ud Here, we report on the partial and full-length genomic (FLG) variability of HTLV-1 sequences from 90 well-characterized subjects, including 48 HTLV-1 asymptomatic carriers (ACs), 35 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 7 adult T-cell leukemia/lymphoma (ATLL) patients, using an Illumina paired-end protocol.\ud Methods\ud \ud Blood samples were collected from 90 individuals, and DNA was extracted from the PBMCs to measure the proviral load and to amplify the HTLV-1 FLG from two overlapping fragments. The amplified PCR products were subjected to deep sequencing. The sequencing data were assembled, aligned, and mapped against the HTLV-1 genome with sufficient genetic resemblance and utilized for further phylogenetic analysis.\ud Results\ud \ud A high-throughput sequencing-by-synthesis instrument was used to obtain an average of 3210- and 5200-fold coverage of the partial (n = 14) and FLG (n = 76) data from the HTLV-1 strains, respectively. The results based on the phylogenetic trees of consensus sequences from partial and FLGs revealed that 86 (95.5%) individuals were infected with the transcontinental sub-subtypes of the cosmopolitan subtype (aA) and that 4 individuals (4.5%) were infected with the Japanese sub-subtypes (aB). A comparison of the nucleotide and amino acids of the FLG between the three clinical settings yielded no correlation between the sequenced genotype and clinical outcomes. The evolutionary relationships among the HTLV sequences were inferred from nucleotide sequence, and the results are consistent with the hypothesis that there were multiple introductions of the transcontinental subtype in Brazil.\ud Conclusions\ud \ud This study has increased the number of subtype aA full-length genomes from 8 to 81 and HTLV-1 aB from 2 to 5 sequences. The overall data confirmed that the cosmopolitan transcontinental sub-subtypes were the most prevalent in the Brazilian population. It is hoped that this valuable genomic data will add to our current understanding of the evolutionary history of this medically important virus.This study was supported with funding from the Fundação de Amparo a Pesquisa do Estado de São Paulo (2011/12297-2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Pathologic and gene expression features of metastatic melanomas to the brain: Biology of Metastatic Melanomas to the Brain

The prognosis of MBM is variable with prolonged survival in a subset. It is unclear whether MBMs differ from extracranial metastases (EcM) and primary melanomas (PrM)

A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35)

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome

Non–small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma

Genetic variation in ESR2 and estrogen receptor-beta expression in lung tumors

Objective: To investigate the association between inherited variation in the estrogen receptor beta (ERβ) gene (ESR2) and ERβ lung tumor expression, a phenotype that possibly affects survival differently in men and women. Methods: We genotyped 135 lung cancer patients for 22 ESR2 single nucleotide polymorphisms (SNPs) and measured nuclear and cytoplasmic ERβ expression by immunohistochemistry (IHC) in their primary lung tumor. Distributing Allred ERβ IHC scores according to ESR2 genotype classified under a dominant genetic model, we used rank sum tests to identify ESR2 SNPs significantly associated (p \u3c 0.05) with ERβ expression. Results: 35%, 35%, and 29% of lung tumors showed no/low (Allred \u3c 6), intermediate (Allred 6-7), and maximal (Allred 8) cytoplasmic ERβ expression, whereas 13%, 27%, and 60% showed no/low, intermediate, and maximal nuclear ERβ expression. For SNPs rs8021944, rs1256061 and rs10146204, ERβ expression was higher according to the rank sum test in lung tumors from patients with at least one minor allele. For each of these three SNPs, the odds of maximal (Allred 8) relative to no/low (Allred \u3c 6) ERβ expression was 3-fold higher in tumors from patients with at least one minor allele than in tumors from patients homozygous for the common allele. Conclusion: Inherited variability in ESR2 may determine ERβ lung tumor expression. © 2013 Elsevier Ltd

MicroRNA expression profiling predicts clinical outcome of carboplatin/paclitaxel-based therapy in metastatic melanoma treated on the ECOG-ACRIN trial E2603

Background\ud Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18–20 % in unselected chemotherapy-naïve patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index.\ud \ud Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree-guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [2] for network inference.\ud \ud Results\ud T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease.\ud \ud Conclusions\ud This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection